Synthesis of a series of nitrothiophenes with basic or electrophilic substituents and evaluation as radiosensitizers and as bioreductively activated cytotoxins.
Synthesis of a series of nitrothiophenes with basic or electrophilic substituents and evaluation as radiosensitizers and as bioreductively activated cytotoxins.
复制标题
合成一系列具有碱性或亲电取代基的硝基噻吩，并评估其作为放射增敏剂和生物还原激活的细胞毒素的作用。
DOI：
10.1021/jm00111a029
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发表时间：
1991
影响因子：
7.3
通讯作者：
Fielden,EM
中科院分区：
文献类型：
--
作者：
Threadgill,MD;Webb,P;O'Neill,P;Naylor,MA;Stephens,MA;Stratford,IJ;Cole,S;Adams,GE;Fielden,EM
以噻吩甲酰氯为原料，与适当的氨基烷基胺反应，合成了一系列含N-（γ-氨基烷基）侧链的2-和3-硝基噻吩-5-甲酰胺。通过相应的N-烯丙基酰胺的环氧化合成了类似的N-（环氧乙烷基甲基）硝基噻吩-5-甲酰胺。这两类化合物在体外进行了评价，作为低氧哺乳动物细胞的放射增敏剂和作为选择性生物还原活化的细胞毒素。最有效的放射增敏剂是那些在侧链中具有强叔胺碱或环氧乙烷的药剂。体内研究表明，2-甲基-N-[2-（二甲基氨基）乙基]-3-硝基噻吩-5-甲酰胺在给予0.34 mmol kg-1的小鼠中引起KHT肉瘤的轻微放射增敏。然而，在较高剂量下给予这种和相关的叔胺会因全身毒性而被排除，实体瘤缺氧区细胞对电离辐射杀伤的相对抵抗性仍然是放射治疗局部控制癌症失败的重要原因，因为分子氧是DNA损伤的表现形式所必需的电子受体。然而，亲电子硝基杂环可以充当
A series of 2-and 3-nitrothiophene-5-carboxamides bearing N-(y-aminoalkyl) side chains has been prepared by treatment of the thiophenecarbonyl chloride with the appropriate (protected)-aminoalkylamine. Analogous N-(oxiranylmethyl) nitrothiophene-5-carboxamides have been synthesized by epoxidation of the corresponding jV-allylamide. Compounds in both classes were evaluated in vitro both as radiosensitizers of hypoxic mammalian cells and as selective bioreductively activated cytotoxins. The most potent radiosensitizers were those agents with strong tertiary amine bases or oxiranes in the side chain. Studies in vivo showed that 2-methyl-JV-[2-(dimethyl-amino) ethyl]-3-nitrothiophene-5-carboxamide caused slight radiosensitization of the KHT sarcoma in mice given 0.34 mmol kg'1. However, administration of this and related tertiary amines at higher doses was precluded by systemic toxicity.The relativeresistance of cells in hypoxicregions of solid tumors to killing by ionizing radiation remains an im-portant reason for failure of local control of cancer by radiotherapy since molecular oxygen is required as an electron acceptor for the manifestation of damage to DNA. Electron-affinic nitroheterocycles can, however, act as